Acid and ester intermediates for preparing 3,4-bisnor-5-aza-b-homopregnane-2,20-diones

ABSTRACT

WHEREIN R is H or CH3 and is H, Y being H only when R is H. This invention relates to the preparation of steroids having the formula

United States Patent 15 3,696,109 Levine 51 Oct. 3, 1972 s41 ACID ANDESTER INTERMEDIATES OTHER PUBLICATIONS FOR PREPARING 3,4-BISNOR-5-AZA-B-HOMOPREGNANE-2,20-DIONES [72] Inventor: Seymour D. Levine, North Bruns-WEEK-112 992 [73] Assignee: E. R. Squibb & Sons, Inc., New

York,N.Y. [22] Filed: May 14, 1970 [21] Appl. No.: 48,727

Related US. Application Data [62] Division of Ser. No. 686,744, Nov. 29,1967,

Pat. No. 3,557,087.

[52] US. Cl. ..260/287 R [51] Int. Cl. ..C07d 33/02 [58] Field of Search..260/289 AZ, 239 A, 239 BB, 260/287 R [5 6] References Cited UNITEDSTATES PATENTS 3,022,312 2/1962 Wildi ..260/287 X 3,280,133 10/1916Pappo et a1. ..260/287 X 3,290,287 12/1966 Mazur et a1 ..260/287 X3,567,733 3/1971 Nomine et a1. ..260/287 3,590,031 6/1971 Levine..260/287 X 3,389,140 6/1968 Montzka ..260/287 R 3,652,544 3/ 1972Levine ..260/289 Z Nelson et a1., Jour. Org. Chem. Vol. 26, p. 3,086-3,089(1961) Primary Examiner-Donald G. Daub Attorney-Lawrence S.Levinson and Merle J. Smith ABSTRACT This invention relates to thepreparation of steroids having the formula wherein R is or o H, Y beingH only when R is H.

3 Claims, N0 Drawings ACID AND ESTER INTERMEDIATES FOR PREPARING3,4-BISNOR-5-AZA-B- HOMOPREGNANE-2,20-DIONES This is a division ofapplication .Ser. No. 686,744, filed Nov. 29, i967 now US. Pat. No.3,557,087 granted Jan. 19, 1971.

This invention relates to and has as its objective the provision ofnovel physiologically active steroids and new intermediates useful inthe preparation thereof.

The final products of this invention can be represented by the generalformula:

wherein n represents 1 or 2.

The final products of this invention are physiologically activesubstances useful in both human and veterinary medicine. They are highlyuseful agents in inhibiting or counteracting the effects of androgens(being therefore called anti-androgens) such as testosterone. Forexample, abatement of skin eruptions in cases of hyperandrogenic acne(the acne conditionresulting from the overabundance of an androgen suchas testosterone) may be achieved by the peroral administration of theanti-androgens of this invention in dosages of from about to 200 mg./kg.of body weight daily. They may also be administered systemically (e.g.,subcutaneously) in a dosage of from about 2 to 60 mg./kg. of body weightdaily. Further topical application may be employed in the treatment ofthis condition, utilizing, for instance, a cream or lotion containingfrom about 1 to 25 percent of the final product of this invention.

As anti-androgens, the final products of this invention have been foundto be useful in veterinary medicine. Male swine, the meat of which isusually rendered unpalatable by a characteristic odor developed by themature animal which permeates the meat, may be treated with the finalproducts of this invention in order to suppress the formation of theodor and hence render the meat more palatable. Likewise the caponizingof male chickens may be achieved without resort to castration by meansof administration of the final products of this invention. For thesepurposes they may be administered orally at a dosage of about 10 to 200mgJkg. of body weight daily, or parenterally at a dosage of about 2 to60 mg./kg. of body weight daily.

Perorally acceptable formulations can beprepared in the usual manner toprovide an aqueous suspension, an elixir or a solid dosage unit form(e.g., tablet, powder or capsule), for example, two-piece hard gelatincapsules may be filled with a mixture of the active ingredient andexcipients (e.g., starch, talc, stearic acid, and/or magnesiumstearate). Also one-piece gelatin capsules containing the same amount ofmedicament may be prepared using sufficient corn oil or other suitablevegetable oil to render the compound capsulatable. Tablets may beprepared by using starch, lactose or other conventional excipients, andmay 'be scored to enable the administration of fractional dosages, ifdesired. Any of the tableting material used in pharmaceutical practicemay beemployed. Liquid preparations may be in the form of suspensions,emulsions, syrups or elixirs of the active substance in water or otherliquid medium commonly used for making orally acceptable pharmaceuticalformulations, such as liquid paraffin, or a syrup elixir base.

The final products of this invention may be formulated into apreparation suitable for topical administration in conventional mannerwith the aid of one or more carriers of excipients. Examples of types oftopical formulation include ointments, creams, sprays, aersols, and thelike. Ointments and creams may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agents. Such bases may, for example, include water and/or an oilsuch as liquid paraffin or a vegetable oil such as caster oil, arachisoil, or the like. Various thickening agents may be employed inapcordance with thenature of the base, for example, soft paraffin,aluminum stearate, cetostearyl alcohols, polyethylene glycols, woolfat,hydrogenated lanolin, and the like.

Lotions may likewise be formulated with an aqueous or oily base and willin general also include various emulsifying agents, dispersing agents,suspending agents, thickening agents, coloring agents, perfumes, and thelike.

In addition, the compounds of this invention (both intermediate andfinal products) are surface active agents which may therefore beemployed in a variety of applications requiring suchan agent. Forexample, the,

compounds of this invention may be employed as emulsifying agents in thepreparation of lubricants, adhesives, polishes, wax compositions, andthe like. For these purposes the compounds of this invention may beemployed in concentrations of about 0.5 to about 20.0 weight percentbased upon the total composition. (e. g.,

They may also be employed as antioxidants and corrosion inhibitors forvarious hydrocarbons and mixtures thereof. As examples of materials towhich the compounds of this invention may be added for this purpose maybe mentioned gasoline, hydrocarbon lubricating oils and greases,hydrocarbon solvents (e. g., toluene, kerosene), rubber, polyolefinplastics (e.g., polyethylene, polypropylene) and the like. For thispurpose they may be employed in concentrations ranging from about 0.01to about 1.0 weight percent based upon the total composition.

The final products of this invention may be prepared beginning witheither A-norprogesterone or A-nor-B- norprogesterone in accordance withthe following reaction schema, wherein Ac represents acetyl, and nrepresents 1 2: 2;

I II

CH: i F

/ l \:l O

o- H2) H2)n III W CH3 CH3 0 M l\0 Role Y L CHaOzK l EN (112) -v CH2-)I1HO-N V VI R=H VII R=CH3 CH: CH H$-OAO H oH N AC( N H2)n HO HN H1)nCHS-C/V ll VIII IX CH3 CH H -OH =0 L 0:11 HO N (112) N 2)n cm-c cH.-( J

X XI

CH CH3 nozc Hole Y N H2) HN Hz) CH -C XIV In this application and in theappended claims, whenever in the formulas set forth herein, a wavy lineis employed in the linkage of atoms, it is meant to denote that theconnected atom may be either in the alpha or beta position.

In the following description the preparation of the final products ofthis invention will be described employing A-norprogesterone as astarting material. The use of A-norprogesterone results in a finalproduct possessing a seven-membered B-ring. It will be understood,however, that the preparation of compounds of this invention possessinga six-membered B-ring is achieved by the substitution ofA-nor-B-norprogesterone as the starting material, all describedreactions being carried out in the same manner as set forth below.A-norprogesterone is of course well known, F. L. Weisenborn and H. E.Applegate, JACS, 81, 1960 (1959). A- nor-B-norprogesterone has beendisclosed in U. S. Pat. No. 3,331,868, issued to Holden et al. on July18, 1967.

In the first step of the process of this invention, A- norprogesterone(I) is treated with potassium permanganate-sodium metaperiodate inaccordance with the procedure set forth in Example 1 of applicantscopending application, Ser. No. 534,997, filed Mar. 17, 1966, now US.Pat. No. 3,557,087 to produce 3-oxa- A-norpregnane-5B-ol-2,20-dione(II). Alternatively, Compound Il may be prepared by hydroxylation of A-norprogesterone (I) with osmium tetroxide followed by oxidation withperiodic acid. The lactonol (II) thus prepared is then ketalized withethylene glycol in the presence of p-toluenesulfonic acid to giveCompound III.

Compound III may be esterified with diazomethane to give the methylester (IV).

The ester may then be treated with hydroxylamine hydrochloride inpyridine at room temperature to afford the oxime (V).

Beckman rearrangement of the oxime (with thionyl chloride in dioxane)followed by hydrolysis with 25 percent aqueous potassium hydroxidesolution gives the lactam acid (VI) which is then esterified withdiazomethane to produce the methyl ester (VII).

Reduction of Compound VII with lithium aluminum hydride intetrahydrofuran gives the dihydroxy amine (VIII).

Compound VIII is then acetylated with acetic anhydride in pyridine toobtain the N-acetyl diacetate (IX) which is selectively hydrolyzed withpotassium carbonate in methanol to the N-acetyl diol (X).

Oxidation of Compound X with Jones reagent (CrO -,--H SO at ice bathtemperature gives the N- acetyl aldehyde (X1) which is then treated withsilver oxide at room temperature to produce the N-acetyl amino acid(XII). If desired, Compound XII may then be esterified with diazomethaneto produce Compound XIII.

Compounds XII or XIII may be refluxed in dioxane containing concentratedhydrochloric acid to remove the acetyl group, thus forming theamino acid(XIV).

The amino acid is then cyclized by treatment at room temperature withdicyclohexylcarbodiimide in nitromethane to produce the steroidalB-lactam (XV), which is a final product of this invention.

The invention may be illustrated by the following examples wherein alltemperatures are in degrees Centigrade:

EXAMPLE 1 3-Oxa-A-norpregnane-5B-ol-2,20-dione 20 ethylene ketal Asolution of 200 mg. of 3-oxa-A-norpregnane-5B- ol-2,20-dione in 2 ml. ofethylene glycol and 35 ml. of benzene containing mg. ofp-toluenesulfonic acid is stirred and refluxed for 5 hours. The reactionmixture is diluted with water and the benzene layer separated. Theaqueous phase is extracted with additional benzene. The combined benzeneextracts are evaporated to give 3-oxa-A-norpregnane-5B-ol-2,20 dione-ethylene ketal.

EXAMPLE 2 Methyl 2,5-seco-3,4-bisnorpregnane-5,20-dione 20 ethyleneketal 2-oic Acid A solution of 100 mg. of 3-oxa-A-norpregnane-5 B- ol-2,20-dione 20-ethylene ketal in I ml. of ether and 1 ml. of methanol istreated with an excess of diazomethane in ether and left at roomtemperature for 10 minutes. Acetic acid is added and the mixtureevaporated to give methyl 2,5-seco-3,4-bisnorpregnane-5,20-dione20ethylene ketal 2-oic acid.

EXAMPLE 3 Methyl 5-oximino-2,5-seco-3,4-bisnorpregnane-20-one 20-ethylene ketal-2-oic Acid A solution of l g. of methyl2,5-seco-3,4-bisnorpregnane-5,20-dione 20-ethylene ketal 2-oic acid andl g. of hydroxylamine hydrochloride in 18 ml. of pyridine is left atroom temperature for 3 days. The reaction mixture is diluted with waterand the product collected by filtration to give methyl5-oximino-2,5-seco-3,4- bisnorpregnane-20-one-20-ethylene ketal 2-oicacid.

EXAMPLE 4 2,5-Seco-3,4 bisnor-5-aza-B-homopregnane-6,20- dione 2-oicAcid A solution of 500 mg. of methyl 5-oximino-2,5-seco-3,4-bisnorpregnane-20-one-20-ethylene ketal-2-oic acid in IQ ml. ofdioxane is cooled to a solid mass and treated with 0.5 ml. of thionylchloride. After 0.75 hr. at room temperature, this solution is added to80 ml. of 30 percent aqueous potassium hydroxide and warmed on a steambath for 0.5 hr. The solution is cooled and extracted with ether. Theaqueous phase is acidified with hydrochloric acid and extracted withchloroform. The chloroform extracts are washed with 8 percent saltsolution, dried and evaporated to give 2,5-seco-3,4-

bisnor-5-aza-B-homopregnane-6,20-dione 2-oic acid.

EXAMPLE 5 Methyl 2,5-seco-3,4-bisnor-5-aza-B-homopregnane- 6,20-dione2-oic Acid EXAMPLE 6 2,20B-Dihydroxy-2,5-seco-3,4-bisnor-5-aza-B-homopregnane; 2,20a-dihydroxy-2,5-seco-3,4-bisnor5-aza-B- homopregnane Asolution of 1.4 g. of methyl 2,5-seco-3,4-bisnor-5-aza-B-homopregnane-6,20-dione 2 -oic acid in ml. of tetrahydrofuran istreated with 2.0 g. of lithium aluminum hydride and refluxed for 3 days.Excess hydride is destroyed by the addition of ethyl acetate. Thereaction mixture is treated with 2N sodium hydroxide solution, thelayers separated, and the aqueous phase extracted with additionalchloroform. The combined organic fractions are washed with 8 percentsalt solution, dried and evaporated to give a mixture of 2,203-dihydroxy-and 2,20a-dihydroxy-2,5-seco-3,4-bisnor-5- aza'B-homopregnane,which is separated by chromatography on neutral alumina. If desired,however, and as illustrated, the mixture may be used directly for thenext chemical step.

EXAMPLE 7 N-Acetyl-2,20B-diacetoxy-2,5-seco-3,4-bisnor-5-aza-B-homopregnane; N-Acetyl-2,20a-diacetoxy-2,5-seco-3,4-bisnor-5-aza-B-homopregnane A solution of 1.3 g. of a mixture of 2,2OB-dihydroxyand 2,20a-dihydroxy-2,5-seco-3,4-bisnor-5aza-B- homopregnane in 7 ml. ofacetic anhydride and 7 ml. of pyridine is left at room temperatureovernight. The reaction mixture is diluted with water and extracted withchloroform. The chloroform extracts are washed with 2N HCI water and 8percent salt solution, dried and evaporated to give a mixture ofN-acetyl-2,20B- diacetoxy-and N-acetyl-2,20a-diacetoxy-2,5-seco-3,4-bisnor-S-aza-B-homopregnane, which is separated by chromatography onneutral alumina. As above, the mixture may ,if desired, be used directlyfor the next chemical step.

EXAMPLE 8 N-Acetyl-2,ZOB-dihydroxy-Z,5-seco-3,4-bisnor-5-aza-B-homopregnane;

N-Acetyl-2,20a-dihydroxy2,5-seco-3 ,4- bisnor-S-aza- B-homopregnaneEXAMPLE 9 N-Acetyl-2,5-seco-3,4-bisnor--aza-B-homopregnane- 2al-20- oneA solution of 600 mg. of a mixture of N-acetyl- 2,20B-dihydroxy andN-acetyl 2,20a-dihydroxy-2,5- seco-3,4-bisnor-5-aza-B-homopregnane in 60ml. of acetone is cooled to 3.5 and treated with an excess of Jonesreagent. After 2 hr. at 3.5", methanol is added to decompose excessoxidant and water is added. The organic solvents are evaporated and theaqueous phase extracted with chloroform. The chloroform extracts arewashed with water, 8 percent salt solution, dried and evaporated to giveN-acetyl-2,5-seco-3,4-bisnor-5- aza-B-homopregnane-Z-al--one.

EXAMPLE 10 N-Acetyl-2 ,5-seco-3 ,4-bisnor-5 -aza-B-homopregnan e-20-one- 2-oic Acid A solution of 2.5 g. of silver nitrate in 25 ml. ofwater is added to a solution of 2.5 g. of N-acetyl-2,5-seco-3,4-bisnor-5-aza-B-homopregnane-Z-al-ZO-one in 50 ml. of 95 percent ethanol.This solution is treated dropwise with a solution of 2.5 g. of sodiumhydroxide in 45 ml. of water and the resulting suspension stirred in thedark for 4 hr. The precipitate is removed by filtration and washed withwater and the filtrate is extracted with chloroform. The aqueous phaseis acidified and extracted with chloroform. The chloroform extracts arewashed with 8 percent salt solution, dried and evaporated to giveN-acetyl-2,5-seco-3,4-bisnor-5-aza- B-homopregnane-20-one-2-oic acid.

EXAMPLE I 1 Methyl N-acetyl-2,5-seco-3,4-bisnor-5-aza-B- homopregnane-20-one-2-oic Acid Following the methylation procedure described inExample 2, but substituting an equivalent amount of the product ofExample IQ for the 3-oxa-A-norpregnane-5B-ol-2,20-dione 20-ethyleneketal, there is obtained the title compound.

EXAMPLE l2 2-Carboxy-2,5-seco-3,4-bisnor-5-aza-B- homopregnane-ZO-one Asolution of 400 mg. of N-acetyl-2,5-seco-3,4-bisnor-S-aza-B-homopregnane-20-one-2-oic acid in 0.5 ml. of water, 7.5ml. of concentrated HCl and 25 ml. of dioxane is refluxed for l5 hr. andthen evaporated. The residue is dissolved in water and the pH of thissolution adjusted to pH 5.1 with sodium bicarbonate solution, and 8percent salt solution added. This aqueous solution is extracted withchloroform. The aqueous layer is then adjusted to pH 5.5 and evaporated.The residue is treated with several portions of chloroform. Thechloroform layers are dried and evaporated to give 2-carboxy-2,S-seco-3,4-bisnor-S-aza-B-homopregnane- 20-one.

EXAMPLE l3 3,4-Bisnor-5-aza-B-homopregnane-2,20-dione A solution of 450mg. of 2-carboxy-2,5-seco-3,4- bisnor-5-aza-B-homopregnane-20-one in 15ml. of nitromethane is treated with 270 mg. of dicyclohexylcarbodiimideand stirred at room temperature for two days. The N,N-dicyclohexylureais removed by filtration and the filtrate evaporated. The residue isplate chromatographed on neutral alumina using chloroform-hexane (1:1)as the developing solvent and the major band is detected with iodinevapor. Elution with ethyl acetate and evaporation gives 3,4-bisnor -5-aza-B-homopregnane-20-one.

EXAMPLE l4 3-Oxa-A-nor-B-norpregnane-SB-ol-Z,20-dione A suspension of344 mg. of potassium carbonate, 45 mg. of potassium permanganate and1.42 g. of sodium metaperiodate in 40 ml. of water is added to asolution of 250 mg. of A-nor-B-norprogesterone in 40 ml. of tbutanol andstirred overnight at room temperature. The mixture is diluted withwater, acidified with 2N HCl and extracted with chloroform. Thechloroform extracts are washed with 8 percent salt solution, dried andevaporated to give 3-oxa-A-nor'B-norpregnane-Sfi -ol-2,20-dione.

EXAMPLE l5 EXAMPLE l6 Methyl2,5-seco-3,4-bisnor-B-norpregnane-5,20-dione 20- ethylene ketal 2-oicAcid Following the procedure of Example 2, but substituting anequivalent amount of the product of Example l5 for the3-oxa'A-norpregnane-5B-0l-2,20-dione 2O ethylene ketal, there isobtained the product.

EXAMPLE l7 Methyl 5-oximino-2,5-seco-3,4-bisnor-B-norpregnane- 20-one20-ethylene ketal 2-oic Acid Following the procedure of Example 3, butsubstituting an equivalent amount of the product of Example 16 for themethyl 2,5-seco-3,4-bisnorpregnane-5,20-dione 20 ethylene ketal 2-oicacid, there is obtained the product.

EXAMPLE l8 2,5-Seco-3,4-bisnor--azapregnane-6,20-dione Acid Followingthe procedure of Example 4, but substituting an equivalent amount of theproduct of Example 17 for the methyl5-oximino-2,5-seco-3,4-bisnorpregnane- 20-one 20-ethylene ketal 2-oicacid, there is obtained the product.

2-oic EXAMPLE l9 Methyl 2,5-seco-3,4 bisnor-5-azapregnane-6,20-dione2-oic Acid Following the procedure of Example 2, but substituting anequivalent amount of the product of Example 18 for the3-oxa-A-norpregnane-5B-ol-2,20-dione 20- ethylene ketal, there isobtained the product.

EXAMPLE 2O 2 ,20B,Dihydroxy-2,5-seco-3 ,4-bisnor-5-azapregnane; 2,20a-

Dihydroxy-2,5 seco-3 ,4-bisnor-5-azapregnane Following the procedure ofExample 6, but substituting an equivalent amount of the product ofExample 19 for the methyl 2,5-seco-3,4-bisnor-5-aza-B-homopregnane-6,20-dione 2-oic acid, there is obtained the product.

EXAMPLE 21 N-Acetyl2,20B-diacetoxy-2,5'seco3,4-bisnor-5- azapregnane;N-Acetyl-2,20oz-diacetoxy-2,S-seco-3,4-bisnor-5- azapregnane Followingthe procedure of Example 7, but substituting an equivalent amount of themixture produced in Example 20 for the mixture of 2,2OB-dihydroxy-and2,20a-dihydroxy-2,5-seco-3,4-bisnor-5-aza-B- homopregnane, there isobtained the product.

EXAMPLE 22 EXAMPLE 23 10N-Acetyl-Z,S-seco-3,4-bisnor-S-azapregnane-Z-al-ZO- one Following theprocedure of Example 9, but substituting an equivalent amount of themixture produced in 'Example 22 for the mixture of N-acetyl-2,20,B-dihydroxy-and N-acetyl-2,20a-dihydroxy-2,5-seco-3,4-bisnor-S-aza-B-homopregnane, there is obtained the product.

EXAMPLE 24 N-Acetyl-2,5-seco-3,4-bisnor-5-azapregnane-20-one 2- oic AcidFollowing the procedure of Example 10, but substituting an equivalentamount of the product of Example 23 for theN-acetyl-2,5-seco-3,4-bisnor-5-aza-B- homopregnane-2-al-20-one, there isobtained the product.

EXAMPLE 25 Methyl N-acetyl-2,5-seco-3,4-bisnor-5-azapregnane- 20-one2-oic Acid Following the procedure of Example 2, but substituting anequivalent amount of the product of Example 24 for the3-oxa-A-norpregnane-5B-ol-Z,20 dione 20- ethylene ketal, there isobtained the product.

EXAMPLE 26 2-Carboxy-2,5-seco-3,4-bisnor-5-azapregnane-20-one Followingthe procedure of Example 12, but substituting an equivalent amount ofthe product of Example 25 for the N-acetyl-2,5-seco-3,4-bisnor-5-aza-B-homopregnane-20-one 2-oic acid, there is obtained the product.

EXAMPLE 27 3 ,4-Bisnor-5-azapregnane-2,20-dione Following the procedureof Example 13, but substituting an equivalent amount of the product ofExample 26 for the 2-carboxy-2,5-seco-3,4-bisnor-5-aza-B-homopregnane-20-one, there is obtained the product.

What is claimed is: 1

1. A compound of the formula Hozc Y 2. A compound of the formula CH CHIHozC Y CHIOIC om-c Cm-c 3.Acompound of the formula 15 a= v K50la UNTTEDSTATES PATENT CERTIFICATE OF CORRECTION Patent No. I 3 ,696,l09 DatedOctober 3 1972 Inventor) Seymour D. Levine It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

In the Abstract, insert Y after the phrase: "H or CH and".

In the Abstract, insert or after: 8 CH C Column 2, line 40, delete thefollowing: (e.g.,

Signed and sealed this 20th day of February 1973. v

(SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

2. A compound of the formula
 3. A compound of the formula